Autism is a devastating neurodevelopmental disorder characterized by social impairment, restrictive thinking/repetitive behaviors, and communication impairment presenting before age three. Therapeutic development has been hampered by poor understanding of the underlying pathophysiology. Cerebellar dysfunction has been implicated in autism pathogenesis; however, the precise role for the cerebellum in these disorders remains unclear. Tuberous Sclerosis Complex, a genetic disorder caused by mutation in either Tsc1 or Tsc2, has high rates of autism (~50%). Patients with TSC have significant cerebellar abnormalities, which correlate with the presence of autism in TSC, while functional imaging with cerebellar dysfunction also differentiates TSC patients with autism. To investigate the cerebellar contribution to autistic behaviors, Dr. Tsai generated a mouse model with Tsc1 loss specifically in cerebellar Purkinje cells (PCs). Loss of Tsc1 in PCs was sufficient to generate autistic-like behaviors in mice in addition to abnormal neuronal morphology and impaired electric excitability. As mTOR is elevated with loss of Tsc1, Dr. Tsai treated this model with the mTOR specific inhibitor, rapamycin, which resulted in the prevention of pathological and behavioral abnormalities. These findings lead to the hypothesis that abnormal PC morphology and function contribute to autistic-like phenotypes while also providing the foundation to delineate the neuroanatomical basis and critical periods for development and treatment of autistic-like behaviors. To test these hypotheses, the current mentored training proposal has the following specific aims (1) Determine the molecular and neuroanatomical mechanisms underlying autistic-like behaviors in Purkinje cell-specific Tsc1 mutant mice. (2) Define the critical periods for autistic-like behaviors in Purkinje cell specific Tsc1 mutant mice. (3) Define the cerebellar neuroanatomical underlying autistic-like behaviors. These studies will provide important molecular, behavioral, and neuroanatomical insight into the contribution of cerebellar dysfunction to the pathophysiology of autism while also providing the foundation for rational therapeutic development for these devastating disorders. These studies will be performed under the dual mentorship of Dr. Mustafa Sahin, a pioneer in the understanding of the neurological basis for TSC, and Dr. Wade Regehr, a renowned expert in cerebellar circuitry and physiology. The Department of Neurology will provide a fertile environment to define the cerebellar contribution to autism. Dr. Tsai is a child neurologist who directs the Cerebellar Disorders Clinic at Boston Children's Hospital. His career goal is to become an independent physician-scientist committed to understanding the contribution of cerebellar dysfunction to behavioral, learning, and neurodevelopmental disorders such as autism. This mentored award will provide Dr. Tsai a structured, productive training experience that will bolster his transition to becoming an independent physician-scientist.